This K01 application seeks support for additional research training to enable the candidate to work towards unraveling the genetic basis for comorbidity of substance use disorders and depression (SUDs+D). Specifically, further training is sought in the topics of human molecular genetics and neurobiology of SUD+D, as well as training in the search for endophenotypes relevant to SUDs+D, and the analysis of large quantities of genotyping data. Training is also sought in psychiatric and environmental assessment methods, focusing on stressful childhood experiences. The training goals will be advanced through two research projects. Project 1 is a secondary analysis using samples and data ascertained through two NIDA-funded R01s, and its primary aim is to identify genetic regions harboring risk variants for SUDs+D using genetic linkage methods. Due to the inherent limitations of linkage methods, the identified region will be broad and will likely contain many genes. Project 2 will follow up in narrowing down the genetic regions so as to locate candidate genes, i.e., fine mapping the genes that are predisposing to SUDs+D through linkage disequilibrium methods. It will also focus on testing environmental modifiers such as childhood maltreatment, and will test the effect of sex on disease predisposition. Project 2 will further investigate a gene cluster on chromosome 11q23 which contains four candidate risk genes of SUDs: NCAM1, TTC12, ANKK1 and DRD2. The candidate plans to take didactic coursework at both Yale and off-campus sites to enhance her expertise in conducting psychiatric genetics research. She will be mentored by Drs. Joel Gelernter, Joan Kaufman and Hongyu Zhao. They are all highly regarded scientists and are exceedingly qualified to guide the candidate's career development plan. The ultimate goal is to facilitate the candidate's transition into an independent psychiatric geneticist devoted to finding the genetic and environmental risk factors for the comorbid SUDs and depression and other phenotypes important in psychiatric genetics. PUBLIC HEALTH RELEVANCE: Substance use disorders and depression, which co-occur at a high rate, are psychiatric disorders that have serious consequences for the affected individuals, their families, and all of society. Identifying genetic and environmental causes of this comorbidity can have a significant impact on the design of effective treatments and prevention strategies, and fulfills NIDA's mission.